Glucocerebrosidase enzyme is typically capable of breaking down glucosylceramide into the products glucose and ceramide. Deficiency of glucocerebrosidase, e.g., due to mutation of GBA, can result in clinical phenotypes. Specifically, deficiency of glucocerebrosidase can lead to the progressive accumulation of glucosylceramide within macrophages, predominantly in spleen, liver, and bone marrow, potentially leading to hepatosplenomegaly, anemia, thrombocytopenia, and skeletal involvement.
Gaucher disease is a condition associated with the absence or dysfunction of glucocerebrosidase. The incidence of Gaucher disease is about 1 in 20,000 live births. The most common symptoms of Gaucher disease are enlargement of the liver and spleen, anemia, nose bleeds, reduced platelets (resulting in easy bruising and long clotting times), bone pain (“bone crises”), bone deterioration, bone infarctions often leading to damage to the shoulder or hip joints, and a generalized demineralization of the bones (osteoporosis). The weakening of the bones can then lead to spontaneous fractures. The course of the disease is quite variable: while some affected individuals display no outward symptoms, Gaucher disease can result in severe disability and death in others.
Over 350 mutations of GBA have been detected in patients with Gaucher disease. Missense mutations are the most common type of mutation. Mutations can disrupt trafficking, stability, processing, a variety of other parameters, or a combination thereof. GBA mutations can be classified as mild, severe, or lethal, on the basis of biochemical and physiological outcomes. The estimated prevalence rate of Gaucher disease is 1 in 50,000 to 1 in 100,000 in the general population, and 1 in 855 in the Ashkenazi Jewish population. In individuals of Ashkenazi Jewish descent, the carrier frequency has been estimated to be as high as approximately 1 in 15.
An important treatment for Gaucher disease is enzyme replacement therapy. For example, velaglucerase alfa (trade name VPRIV™), manufactured by Shire plc, is a recombinant form of glucocerebrosidase approved by FDA as a long-term enzyme replacement therapy for those suffering of Gaucher disease.